We describe herein a program directed at the total synthesis of the novel sesquiterpene antineoplastic agent quadrone and the C(1)-alpha-hydroxylated pseudoguaianolides parthenin and coronopilin and the 4,5-secopseudoguaianolide psilostachyin. Quadrone exhibits significant in vitro cytotoxicity against human epidermoid carcinoma of the nasopharynx (KB) with an ED50 of 1.3 microgram/ml an in vivo inhibitory activity against P388 lymphocytic leukemia in mice. Parthenin and coronopilin have been shown to exhibit in vitro cytotoxicity againt KB cell cultures with respective ED50 values of 0.34 microgram/ml and 1.45 microgram/ml. As an integral part of this program, we seek also to apply the technology developed in these studies to the preparation of structural analogs of the above-named compounds, for the purpose of generating modified biological activity. Key areas of investigation will include the following: (1) application and further development of a vinylsilane-mediated spiroannulation; (2) application and refinement of Claisen rearrangement technology for generating beta-alkylidene-alpha, alpha-disubstituted cyclopentanones of predictable and defined sp2- and sp3-carbon stereochemistry; (3) evaluation and development of transition metal-based vicinal functionalization of olefins, and (4) the application and furtherance of a novel intramolecular ring expansion designed to provide seven- (and eight-) membered carbocycles with a high degree of peripheral sp3-carbon stereochemistry and functionality to allow regio-biased elaboration. The proposed synthetic program should provide efficient, stereospecific access to quadrone, parthenin, coronopilin, and psilostachyin, as well as close structural analogs. The synthetic methodology arising from these studies should have broad applicability in organic synthesis.